MnTBAP Ameliorates Obesity and Metabolic Dysfunction and Limits the TF‐PAR2 Pro‐inflammatory Pathway in White Adipose Tissue

Abstract

Obesity is a prevalent metabolic disease that is associated with increased reactive oxygen species and oxidative stress. The purpose of this study was to determine if the superoxide dismutase mimetic manganese tetrakis benzoic acid porphyrin (MnTBAP) can attenuate obesity and obesity-associated metabolic dysfunction. Mice were treated with MnTBAP or vehicle during the last five weeks of a 24 week high fat diet (HFD) regimen. Energy homeostasis, insulin sensitivity, adipose macrophage infiltrates, protein kinase B (PKB) and tissue factor - protease activated receptor 2 (TF-PAR2) pathways were assessed following MnTBAP treatment. MnTBAP treatment significantly reduced body weight and adipose tissue mass. The reduction in adiposity was associated with decreased caloric intake and improved insulin sensitivity. Protein kinase B (PKB) phosphorylation and expression were significantly increased in a tissue-specific manner in skeletal muscle and adipose tissue of HFD mice treated with MnTBAP. In addition, MnTBAP treatment decreased macrophage infiltrates in adipose tissue and reduced the pro-inflammatory TF-PAR2 pathway. Our data suggests that the ability of MnTBAP to improve insulin sensitivity is due to decreased adiposity, reduced adipose tissue inflammation, and increased PKB phosphorylation and expression. Further, our findings implicate decreased caloric intake and inhibition of the TF-PAR2 pathway in the anti-obesity and insulin-sensitizing effects of MnTBAP.